The present invention relates to new cyclobutaindolecarboxamide compounds, and pharmaceutical compositions containing them.
The compounds of the present invention are useful in the treatment of disorders of the central nervous system, such as anxiety, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, cognitive disorders, psychoses, depression and mood disorders.
Numerous polycyclic and heterocyclic compounds containing a urea function have been described in the literature as antagonists of various serotonergic receptors, thus enabling them to be used in the treatment of disorders of the central nervous system. This applies more especially to the Patent Applications WO 95/29177, WO 96/23783 and WO 98/47868, while patent specification U.S. Pat. No. 5,514,690 describes aminocarbonylquinoline and indoline compounds and claims them for their property of activating potassium pumps. In addition to being new, the compounds of the present invention have proved very active in the treatment of disorders of the central nervous system, and more especially have demonstrated strong activity in the Vogel conflict test in the rat, and in the marble-burying test in the mouse. The results obtained in the first test allows the use of the compounds of the invention in the treatment of clinical phenomena associated with anxiety to be proposed, and the results obtained in the second test demonstrates the strong therapeutic potential of the compounds of the invention in the treatment of illnesses associated with mood disorders.
The invention relates more especially to the compounds of formula (I): 
wherein:
n represents an integer of from 0 to 6,
R1 represents a group selected from hydrogen, hydroxy, cyano, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkoxycarbonyl, carboxy, aminocarbonyl (the amino moiety optionally being substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched) and NR4R5 wherein R4 and R5, which may be identical or different, represent a group selected from linear or branched (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, heteroaryl, heteroaryl. (C1-C6)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, cycloalkyl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, linear or branched (C2-C6)alkenyl and linear or branched (C2-C6)alkynyl,
R2 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, hydroxymethyl, a group of formula 
wherein:
T represents a monocyclic or polycyclic (C3-C12)cycloalkyl group, it being possible for one of the carbon atoms of the cycloalkyl optionally to be replaced by a group selected from oxygen, selenium, a group of formula S(O)p wherein p represents an integer of from 0 to 2 inclusive, and a group of formula SiR6R7 wherein R6 and R7, which may be identical or different, represent a linear or branched (C1-C6)alkyl group,
U represents a bond or a methylene group,
V represents a bond, an oxygen atom or a group S(O)q wherein q is an integer of from 0 to 2 inclusive, and
W represents a group selected from aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, and cycloalkyl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched,
and
R3 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, aryl and heteroaryl,
to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base.
An aryl group is to be understood as a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, each of which groups is optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)-alkoxy, nitro, cyano, linear or branched (C1-C6)trihaloalkyl, amino, monoalkylamino, di-(C1-C6)alkylamino in which the alkyl moieties may be linear or branched, (C1-C6)-trihaloalkoxy in which the alkoxy moiety may be linear or branched, amino(C1-C6)alkylaminocarbonyl (the nitrogen atoms of each of the amino moieties optionally being substituted by identical or different linear or branched (C1-C6)alkyl groups), pyridyl, pyridyloxy and pyridyloxymethyl, the latter three groups optionally being substituted by a linear or branched (C1-C6)alkyl group.
A heteroaryl group is to be understood as an aromatic monocyclic system, or a bicyclic system in which one of the rings is aromatic and the other ring is aromatic or partially hydrogenated, having from 5 to 12 ring members and containing one, two or three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, each of the groups optionally being substituted by one or more identical or different groups selected from the substituents described for the aryl group defined above.
A cycloalkyl group is to be understood as a mono- or poly-cyclic system having from 3 to 12 ring members and optionally containing one or more unsaturations, wherein the unsaturations do not confer an aromatic character to the said ring system.
Isomers is to be understood as optical isomers (enantiomers (enantiomers and diastereoisomers).
Amongst the pharmaceuticaly acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, camphoric acid, etc.
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
According to an advantageous embodiment of the invention, preferred compounds of the invention are compounds of formula (I) wherein R2 represents a hydrogen atom.
According to another advantageous embodiment of the invention, preferred compounds of the invention are compounds of formula (I) wherein R2 represents a group of formula 
wherein T is as defined for formula(I), n is 1, and R1 represents a cyano group or an amino group optionally substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched.
In another advantageous embodiment, preferred compounds of the invention are compounds of formula (I) wherein n is 0, R1 represents a hydrogen atom or a cyano group and R2 represents a group of formula -U-V-W wherein U represents a single bond, V represents a group of formula S(O)p wherein p is as defined for formula (I) and W represents an aryl group.
Especially advantageously, preferred compounds of the invention are compounds of formula (I) wherein n is 0, R1 represents a hydrogen atom or a cyano group and R2 represents a hydrogen atom.
The substituent R3 preferred in accordance with the invention is the heteroaryl group and, more especially, the pyridyl group.
The following are preferred compounds of the invention:
N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
5-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
5-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
7-cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide,
7-(hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide,
6-[(dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyano-6-(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyano-N-{6-[(2-methyl-3-pyridyl)oxy]-3-pyridyl}-6-(phenylsulphanyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide.
The isomers of the preferred compounds, and also the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds, form an integral part of the invention.
The invention relates also to a process for the preparation of the compounds of formula (I), which is characterised in that there is used as starting material a compound of formula (II): 
wherein Rxe2x80x21 represents a group selected from hydrogen, cyano, hydroxymethylene, carboxy and linear or branched (C1-C6)alkoxycarbonyl,
which compound of formula (II) is reacted, under the conditions of reductive amination, with a compound of formula (III):
(AO)2CHCHOxe2x80x83xe2x80x83(III)
wherein A represents a linear or branched (C1-C6)alkyl group, to yield the compounds of formula (IV): 
wherein A and Rxe2x80x21 are as defined hereinbefore,
which compounds of formula (IV) are treated with a compound of formula (V):
ClSO2Exe2x80x83xe2x80x83(V)
wherein E represents a linear or branched (C1-C4)alkyl group, phenyl or p-toluyl, to yield the compounds of formula (VI): 
wherein A, E and Rxe2x80x21 are as defined hereinbefore,
which compounds of formula (VI) are cyclised under acid conditions to yield the compounds of formula (VII): 
wherein E and Rxe2x80x21 are as defined hereinbefore,
which compounds of formula (VII) are treated either with an alkali metal hydroxide in an alcoholic solvent or with sodium in liquid ammonia to yield the compounds of formula (VIII): 
wherein Rxe2x80x21 is as defined hereinbefore,
which compounds of formula (VIII) are then reduced, in accordance with the conventional conditions of organic synthesis, to yield the compounds of formula (IX) 
wherein Rxe2x80x21 is as defined hereinbefore,
which compounds of formula (IX) are treated with an isocyanate of formula (X):
R3xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(X)
wherein R3 is as defined for formula (I),
to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein Rxe2x80x21 and R3 are as defined hereinbefore,
or which compounds of formula (IX), in the case where Rxe2x80x21 represents a cyano group, are treated:
either with a ketone of formula (XI): 
wherein T is as defined for formula (I), to yield the compounds of formula (XII): 
wherein T is as defined hereinbefore,
which compounds of formula (XII) are then:
either treated with an isocyanate of formula (X) as described hereinbefore to yield the compounds of formula (I/b), a particular case of the compounds of formula (I), 
xe2x80x83wherein T and R3 are as defined hereinbefore,
or, after protection of the amine of the indoline group, reduced according to the conventional methods of organic synthesis to yield the compounds of formula (XIII): 
wherein T is as defined hereinbefore and P1 is a conventional protecting group, the primary amine function of which compounds of formula (XIII) is then substituted and converted into the secondary and then tertiary amine function, using conventional methods of organic chemistry, to yield the compounds of formula (XIV): 
wherein R4 and R5 are as defined for formula (I) and T and P1 are as defined hereinbefore, which compounds of formula (XIV), after deprotection of the nitrogen atom of the indoline nucleus, are treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/c), a particular case of the compounds of formula (I): 
wherein T, R4, R5 and R3 are as defined hereinbefore,
or with a strong base or an alkali metal alcoholate, in the presence of a compound of formula (XV):
W1xe2x80x94Xxe2x80x83xe2x80x83(XV)
wherein W1 represents a linear or branched (C1-C6)alkyl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, a cycloalkyl group, or a cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, and X represents a leaving group, such as a halogen atom or a trifluoromethylsulphonate, mesylate or tosylate group,
to yield the compounds of formula (XVI): 
wherein W1 is as defined hereinbefore,
which compounds of formula (XVI) are:
either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/d), a particular case of the compounds of formula (I): 
xe2x80x83wherein W1 and R3 are as defined hereinbefore,
or, after protection of the nitrogen atom of the indoline nucleus, converted like the compounds of formula (XII) to primary, secondary and then tertiary amine to yield, after deprotection and treatment in the presence of a compound of formula (X) as described hereinbefore, the compounds of formula (I/e), a particular case of the compounds of formula (I): 
wherein W1, R3, R4 and R5 are as defined hereinbefore,
or with bromine in a chlorine-containing organic solvent to yield the compounds of formula (XVII): 
which compounds of formula (XVII) are reacted with a compound of formula (XVIII):
Wxe2x80x94V1xe2x80x94Hxe2x80x83xe2x80x83(XVIII)
wherein W is as defined for formula (I) and V1 represents an oxygen atom or a sulphur atom,
to yield the compounds of formula (XIX): 
wherein V1 and W are as defined hereinbefore,
which compounds of formula (XIX) are:
either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/f), a particular case of the compounds of formula (I): 
wherein R3, V1 and W are as defined hereinbefore,
which compounds of formula (I/f), in the case where V1 represents a sulphur atom, may be subjected to oxidation under conventional conditions of organic synthesis to yield the compounds of formula (I/g), a particular case of the compounds of formula (I): 
xe2x80x83wherein R3 and W are as defined for formula (I) and q1 is an integer of from 1 to 2 inclusive,
or protected and then converted, by the same sequence of reactions as the compounds of formula (XII), to primary, secondary and tertiary amine to yield, after deprotection and treatment with a compound of formula (X), as described hereinbefore, the compounds of formula (I/h), a particular case of the compounds of formula (I): 
wherein V1, W, R3, R4 and R5 are as defined hereinbefore,
which compounds of formula (I/h), in the case where V1 represents a sulphur atom, may be subjected to oxidation under conventional conditions of organic synthesis to yield the compounds of formula (I/i), a particular case of the compounds of formula (I): 
xe2x80x83wherein W, R3, R4, R5 and q1 are as defined hereinbefore,
or with an alkali metal hydride in dimethylformamide, in the presence of formaldehyde, to yield the compounds of formula (XX): 
xe2x80x83which compounds of formula (XX) are:
either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/j), a particular case of the compounds of formula (I): 
xe2x80x83wherein R3 is as defined for formula (I),
or protected at the nitrogen atom of the indoline nucleus, then treated according to Mitsunobu reaction conditions with a compound of formula (XXI):
Wxe2x80x94OHxe2x80x83xe2x80x83(XXI)
wherein W is as defined for formula (I),
to yield, after deprotection of the nitrogen atom of the indoline nucleus, the compounds of formula (XXII): 
wherein W is as defined hereinbefore,
which compounds of formula (XXII) are:
either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/k), a particular case of the compounds of formula (I): 
xe2x80x83wherein R3 and W are as defined hereinbefore,
or protected and then converted, by the same reaction sequence as the compounds of formula (XII), to primary, secondary and tertiary amine to yield, after deprotection and treatment with a compound of formula (X), as described hereinbefore, the compounds of formula (I/l), a particular case of the compounds of formula (I): 
wherein R3, R4, R5 and W are as defined hereinbefore,
the compounds (I/a) to (I/l) constituting the totality of the compounds of the invention, which compounds are purified, if necessary, according to a conventional purification technique, may be separated, if desired, into their different isomers according to a conventional separation technique, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (III), (V), (X), (XI), (XV), (XVIII) and (XXI) are either known products, or products obtained from known substances according to conventional procedures in organic chemistry.
In view of their pharmacological properties, the compounds of the present invention are useful as medicaments in the treatment of anxiety, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, cognitive disorders, psychoses, depression, and mood disorders.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
The useful dosage varies in accordance with the age and weight of the patient, the administration route, the nature and severity of the disorder and the administration of possible associated treatments and ranges from 0.5 mg to 25 mg in one or more administrations per day.